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WO 2015/153102 Al 8 October 2015 (08.10.2015) P O P C T

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WO 2015/153102 Al 8 October 2015 (08.10.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/153102 Al 8 October 2015 (08.10.2015) P O P C T (51) International Patent Classification: 62/006,832 2 June 2014 (02.06.2014) US A61K 39/00 (2006.01) C12N 5/(97 (2010.01) 62/006,828 2 June 2014 (02.06.2014) u s A61K 35/12 (2015.01) 62/006,825 2 June 2014 (02.06.2014) u s 62/006,829 2 June 2014 (02.06.2014) u s (21) Number: International Application 62/025,367 16 July 2014 (16.07.2014) u s PCT/US20 15/0206 14 62/059,100 2 October 2014 (02. 10.2014) u s (22) International Filing Date: PCT/US201 4/065304 13 March 2015 (13.03.2015) 12 November 2014 (12. 11.2014) u s (25) Filing Language: English (71) Applicant: RUBIUS THERAPEUTICS, INC. [US/US]; 1 Memorial Drive, 7th Floor, Cambridge, MA 02 142 (US). (26) Publication Language: English (72) Inventors: MATA-FINK, Jordi; c/o Rubius Therapeutics, (30) Priority Data: Inc., 1 Memorial Drive, 7th Floor, Cambridge, MA 02142 61/973,763 1 April 2014 (01.04.2014) US (US). ROUND, John; c/o Rubius Therapeutics, Inc., 1 61/973,764 1 April 2014 (01.04.2014) US Memorial Drive, 7th Floor, Cambridge, MA 02142 (US). 61/991,3 19 9 May 2014 (09.05.2014) US AFEYAN, Noubar, B.; c/o Rubius Therapeutics, Inc., 1 [Continued on nextpage] (54) Title: METHODS AND COMPOSITIONS FOR IMMUNOMODULATION (57) Abstract: Provided are cells containing exogenous antigen and uses thereof. IC binding Fig 6A 25000 ■ C s only 20000 BSA+ gG Fig 6B Memorial Drive, 7th Floor, Cambridge, MA 02142 (US). (84) Designated States (unless otherwise indicated, for every KAHVEJIAN, Avak; c/o Rubius Therapeutics, Inc., 1 kind of regional protection available): ARIPO (BW, GH, Memorial Drive, 7th Floor, Cambridge, MA 02142 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (74) Agents: Lando HANNAH KOYFMAN, Ph. D. et al; & TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Anastasi, LLP, One Main Street, Cambridge, MA 02142 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, (US). LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, (81) Designated States (unless otherwise indicated, for every SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, kind of national protection available): AE, AG, AL, AM, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, Published: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, — with international search report (Art. 21(3)) GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, — before the expiration of the time limit for amending the KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, claims and to be republished in the event of receipt of ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, amendments (Rule 48.2(h)) NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. METHODS AND COMPOSITIONS FOR IMMUNOMODULATION FIELD OF THE INVENTION [0001] The field of the invention is pharmaceutical compositions for the treatment of diseases and disorders. BACKGROUND OF THE INVENTION [0002] Aberrant immune activation is a hallmark of many human diseases and conditions. Autoimmune diseases arise when the body's immune system improperly senses an autologous antigen as non-self and attacks the body's own tissues. Inflammatory diseases and allergies can arise when the body's immune system is improperly triggered by common food-borne or environmental antigens. Polypeptides and proteins used to treat a range of human diseases are often destroyed, neutralized, or otherwise rendered ineffective by immune cells that respond to them as though they were foreign antigens. [0003] Current treatment of diseases of improper immune activation involves immunosuppression with chemical agents like corticosteroids, or inhibitors of inflammatory mediators like anti-histamines, antibodies, or cytokines. These generalized treatments are associated with significant morbidities, such as susceptibility to infection, because they broadly suppress the immune system. [0004] For some severe allergies, clinical testing is underway to induce "tolerance" to allergens by exposure to slowly increasing doses of the offending protein over time. To date theses treatments lack long-term efficacy and are associated with a risk of severe anaphylaxis. [0005] There is a need for novel therapeutics to treat these diseases. SUMMARY OF THE INVENTION The invention, in certain aspects, relates to isolated enucleated hematopoietic cells expressing an antigen. Enucleated hematopoietic cells will be referred to herein as "EHCs" (or in its singular form: "EHC"). In some embodiments, the enucleated hematopoietic cells or EHCs lack nuclear material. For example, the EHCs can be are erythroid cells or thromboid cells. In some embodiments, EHCs lacking nuclear material are red blood cells, erythrocytes, reticulocytes, or platelets. In some embodiments, the enucleated hematopoietic cells or EHCs are nucleated precursor erythroid cells or precursor thromboid cells that are, e.g., induced to lose their nuclear material or are rendered functionally enucleated and incapable of replication. In some embodiments, the exogenous antigen-expressing EHC is a circulating cell, such as a red blood cell. In some embodiments, the exogenous antigen-expressing EHC is cultured from a hematopoietic precursor using defined factors. In some embodiments, the exogenous antigen-expressing EHC is a thromboid cell, such as a platelet. In some embodiments the thromboid cell is cultured from a hematopoietic precursor using defined factors. In some embodiments, the exogenous antigen-expressing EHC is a primary cell isolated from a patient, for either autologous or allogeneic use, that is contacted with an antigen. [0006] Certain aspects of the invention relate to exogenous antigen-expressing EHCs that are capable of inducing immune tolerance when administered to a subject, e.g. in form of a pharmaceutical composition comprising the exogenous antigen-expressing EHCs. The exogenous antigen expressed by the EHCs can be tailored to a specific disease, disorder or condition. The exogenous antigen-expressing EHCs can comprise antigen in multiple ways, such as e.g. surface display, intracellular expression, intracellular loading, or surface conjugation, of the antigen of interest. The exogenous antigen-expressing EHCs may manage diseases of aberrant immune activation more effectively and/or with fewer side effects than existing treatments. For example, exogenous antigen-expressing EHCs may selectively modulate the immune system while leaving the broader immune system physiology substantially unperturbed. In some embodiments, exogenous antigen-expressing EHCs may induce the destruction, deactivation, and/or anergy of antigen-specific T and B lymphocytes. Alternatively or in addition, exogenous antigen-expressing EHCs may induce the proliferation of antigen-specific regulatory T lymphocytes. [0007] Certain aspects of the invention relate to exogenous antigen-expressing EHCs that comprise exogenous antigen that is recognized by immune cells in autoimmune diseases, such as, e.g. multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and membranous nephritis. [0008] Certain aspects of the invention relate to exogenous antigen-expressing EHCs that comprise exogenous antigen that is recognized by immune cells in inflammatory diseases, such as, e.g. Crohn's disease, ulcerative colitis, celiac disease, or other idiopathic inflammatory bowl diseases. [0009] Certain aspects of the invention relate to exogenous antigen-expressing EHCs that comprise exogenous antigen that is recognized by immune cells in human leukocyte antigen (HLA) mismatch-mediated diseases, such as, e.g. graft-versus-host disease or organ transplant rejection. [0010] Certain aspects of the invention relate to exogenous antigen-expressing EHCs that comprise exogenous antigen that is recognized by immune cells in allergic diseases, such as, e.g. asthma, peanut allergy, shellfish allergy, pollen allergy, milk protein allergy, insect sting allergy, and latex allergy. [0011] Certain aspects of the invention relate to exogenous antigen-expressing EHCs that comprise exogenous antigen that is a therapeutic protein whose efficacy or potency is reduced or impaired by immune cells, such as, e.g., clotting factor VIII in hemophilia A, clotting factor IX in hemophilia B, anti-tumor necrosis factor alpha (TNFa) antibodies in rheumatoid arthritis and other inflammatory diseases, glucocerebrosidase in Gaucher' s disease, or asparaginase in acute lymphoblastic leukemia (ALL). [0012] Certain aspects of the invention relate to exogenous antigen-expressing EHCs that comprise exogenous antigen that comprises full-length, truncations, and chimeric fusions of polypeptides that a) mediate complement regulation, b) that mediate binding and sequestration of immune complexes, c) autoimmune antibodies, or d) pathogenic particles. In some embodiments, the exogenous antigen comprises full-length, truncations, and chimeric fusions of polypeptides that are enzymatically active in the conversion of one small molecule substrate into another small molecule product or of one polypetide substrate into a second polypeptide product, including, e.g., cleavage of the polypeptide substrate. [0013] The invention, in certain aspects, also provides methods of treatment of disease using the exogenous antigen-expressing EHCs and pharmaceutical compositions thereof provided herein. [0014] In some aspects, disclosed herein is a method of inducing immune tolerance. The method comprises administering to a human subject suffering from or at risk of developing an autoimmune disease, disorder or condition, a pharmaceutical composition comprising an enucleated hematopoietic cell expressing an exogenous antigen, wherein the pharmaceutical composition is administered in an amount effective to induce immune tolerance in the subject to the antigen mediating the autoimmune disease, disorder or condition.
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